The vagal nerves are the largest and most evolved nerves in the human body. They perform mostly sensory and parasympathetic functions within the autonomic nervous system, using acetylcholine (ACh) as the sole neurotransmitter. The left vagus nerve is a mixed nerve with ˜100,000 axons, of which an estimated 65-80% are visceral afferent sensory fibers with sensory receptors located within the aorta, gastrointestinal tract, heart, lungs and esophagus, among others. See J. O. Foley, and F. DuBois, “Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory to motor fibers,” J Comp Neurol, vol. 67, pp. 49-97, 1937; and P. Rutecki, “Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation,” Epilepsia, vol. 31, pp. S1-S6, 1990. Vagal efferents are myelinated and originate primarily from the dorsal motor nucleus (DMN) of the vagus. See P. Rutecki, “Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation,” Epilepsia, vol. 31, pp. S1-S6, 1990. The afferent fibers project primarily to the nucleus tractus solitarius (NTS), where diffuse projections convey the visceral (and some somatic) sensory information throughout the central nervous system (CNS), including areas in the limbic system and cortex that regulate emotion. See U. N. Das, “Vagus nerve stimulation, depression, and inflammation,” Neuropsychopharmacology, vol. 32, pp. 2053-2054, 2007. Many of the afferent fibers participate in autonomic reflexes involved in maintaining homeostasis and have myelinated projections from the nodose ganglion to the NTS, DMN, area postrema, nucleus cunneatus and the medial reticular formation (The nodose ganglion comprises the somata of unipolar sensory neurons, with unmyelinated projections inferior to and myelinated projections superior to the nodose ganglion, respectively). See A. S. Paintal, “Vagal sensory receptors and their reflex effects,” Physiol Rev, vol. 53, pp. 159-227, 1973. The NTS directly communicates with the reticular formation, area postrema and DMN; it also indirectly communicates with the thalamus, hypothalamus, amygdala, cingulate gyms, and orbitofrontal cortex via the locus coeruleus (LC) and parabrachial nucleus (PB). See M. S. George, and G. Aston-Jones, “Noninvasive techniques for probing neurocircuitry and treating illness: Vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct cunent stimulation (tDCS),” Neuropsychopharmacology REVIEWS, vol. 35, pp. 301-316, 2010; and M. S. George, Z. Nahas, J. J. Borckardt et al., “Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders,” Expert Rev. Neurotherapeutics, vol. 7, no. 1, pp. 1-12, 2007.
FIGS. 7A through 7C depict various implementations of VNS devices with associated implant locations according to prior art. FIG. 7A depicts a VNS device housing and electrode implant location. See M. S. George, H. A. Sackeim, A. J. Rush et al., “Vagus nerve stimulation: A new tool for brain research and therapy,” Biol Psychiatry, vol. 47, pp. 287-295, 2000. FIG. 7B depicts a cross-section of a human brainstem showing the primary sites of vagal input (the NTS, or “solitary tract”) and output (the DMN, or “dorsal nuc. of X”). See Id. Referring to FIG. 7C, a summary of NTS efferent projections that impart diffuse, nerve activation level and rate-dependent effects on CNS function is depicted. See M. S. George, Z. Nahas, J. J. Borckardt et al., “Vagus nerve stimulation for the treatment of depression and other neuropsychiatfic disorders,” Expert Rev. Neurotherapeutics, vol. 7, no. 1, pp. 1-12, 2007. The NTS projects to the LC, where effective vagus nerve stimulation is believed to excite noradrenergic neurons, resulting in norepinephfine release in several structures of the limbic system and frontal lobe implicated in temporal lobe epilepsy (TLE) and major depressive disorder (MDD). This has been found to suppress inflammation in the CNS associated with Alzheimer's disease. See M. T. Heneka, F. Nadfigny, T. Regen et al., “Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephfine,” PNAS, vol. 107, no. 13, pp. 6058-6063, 2010.
Vagus nerve stimulation (VNS) has been available since 1994 in Europe and 1997 in the United States as a therapy for treatment-resistant partial onset seizures, where it has helped tens of thousands of patients with drug-resistant TLE experience significant seizure rate reductions. The prospect of using VNS as an alternative therapy for refractory MDD originated from unexpected patient-reported mood improvements observed in the NeuroCybernetic Prosthesis System trials in the 1990s and the off-label uses of specific seizure medications for stabilizing mood disorders. See M. S. George, H. A. Sackeim, A. J. Rush et al., “Vagus nerve stimulation: A new tool for brain research and therapy,” Biol Psychiatry, vol. 47, pp. 287-295, 2000; E. BenMenachem, R. Manon-Espaillat, R. Ristanovic et al., “Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effects on seizures,” Epilepsia, vol. 35, no. 3, pp. 616-626, 1994; J. C. Ballenger, and R. M. Post, “Carbamazepine in manic-depressive illness: a new treatment,” Am J Psychiatry, vol. 137, pp. 782-790, 1980; and R. M. Post, T. W. Uhde, P. P. Roy-Byrne et al., “Antidepressant effects of carbamazepine,” Am J Psychiatry, vol. 143, pp. 29-34, 1986. Several treatment-resistant epileptic patients implanted with the VNS device reported significant mood elevations that researchers could not solely attribute to seizure frequency reduction. Additional positron-emission tomography (PET) studies showed that VNS reduced cingulate activity, the same effect seen from many successful antidepressant therapies, and altered blood flow and metabolism in limbic structures. See M. S. George, H. A. Sackeim, A. J. Rush et al., “Vagus nerve stimulation: A new tool for brain research and therapy,” Biol Psychiatry, vol. 47, pp. 287-295, 2000; and T. R. Henry, R. A. E. Bakay, J. R. Votaw et al., “Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. Acute effects at high and low levels of stimulation,” Epilepsia, vol. 39, no. 9, pp. 983-990, 1998. Researchers have also shown that long-term VNS, for durations of 10 weeks or greater, produces widespread inhibitory effects in the CNS. Specifically, Lazzaro and colleagues applied transcranial magnetic stimulation (TMS) over the motor cortex and demonstrated that long-term VNS produced significant decreases in motor cortical excitability in epileptic patients (in 2007, this experiment was repeated in VNS device recipients with MDD, where the same reductions in cortical excitability were observed). See V. Di Lazzaro, A. Oliviera, F. Pilato et al., “Effects of vagus nerve stimulation on cortical excitability in epileptic patients,” Neurology, vol. 62, no. 12, pp. 2310-2312, 2004; and M. Bajbouj, J. Gallinat, U. E. Lang et al., “Motor cortex excitability after vagus nerve stimulation in major depression,” J Clin Psychopharmacol., vol. 27, no. 2, pp. 156-159, 2007. Other investigations indicated that neurotransmitter levels are altered as a result of VNS. See E. Ben-Menachem, A. Hamberger, T. Hedner et al., “Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures,” Epilepsy Research, vol. 20, no. 3, pp. 221-227, 1995; and S. E. Krahl, K. B. Clark, D. C. Smith et al., “Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation,” Epilepsia, vol. 39, no. 7, pp. 709-714, 1998. Due to this observation and the unexpected reports of mood improvement, the first VNS device for the treatment of unipolar refractory MDD was implanted by Rush and colleagues in 1998. See M. S. George, H. A. Sackeim, A. J. Rush et al., “Vagus nerve stimulation: A new tool for brain research and therapy,” Biol Psychiatry, vol. 47, pp. 287-295, 2000; and A. J. Rush, M. S. George, H. A. Sackeim et al., “Vagus Nerve Stimulation (VNS) for treatment-resistant depressions: A multicenter study,” Biol Psychiatry, vol. 47, pp. 276-286, 2000. Response rates (i.e., A patient is a responder if a standardized depression rating scale score is reduced by >50% in response to the therapy) of 27-40% were observed after at least 8 weeks of VNS therapy; robust and durable antidepressant responses are seen after 12 or more months of VNS therapy. See M. S. George, Z. Nahas, D. E. Bohning et al., “Vagus nerve stimulation therapy: A research update,” Neurology, vol. 59, no. Suppl. 4, pp. S56-S61, 2002; and M. S. George, A. J. Rush, L. B. Marangell et al., “A one-year companson of vagus nerve stimulation with treatment as usual for treatment-resistant depression,” Biol Psychiatry, vol. 58, pp. 364-373, 2005. The FDA approved VNS for refractory MDD in July 2005. See M. S. George, H. A. Sackeim, A. J. Rush et al., “Vagus nerve stimulation: A new tool for brain research and therapy,” Biol Psychiatry, vol. 47, pp. 287-295, 2000; C. B. Nemeroff, H. S. Mayberg, S. E. Krahl et al., “VNS therapy in treatment-resistant depression: Clinical evidence and putative neurobiological mechanisms,” Neuropsychopharmacology, vol. 31, pp. 1345-1355, 2006.
The VNS device implant procedure is rather straightforward. Under general anesthesia, the VNS device housing is surgically implanted in the left chest wall. A projecting stimulation lead with an attached helical electrode is then wrapped around the left cervical vagus nerve and secured to surrounding tissue. The device is externally activated and programmed using a wand like device placed over the left chest wall. Stimulation is intermittent and commonly programmed for 30 s of monophasic, constant-current stimulation every 5 min. However, individual parameters are adjusted on a patient-to-patient basis in order to achieve maximal therapeutic efficacy with minimal side effects. See L. B. Marangell, M. Martinez, R. A. Jurdi et al., “Neurostimulation therapies in depression: A review of new modalities,” Acta Psychiatrica Scandinavica, vol. 116, pp. 174-181, 2007. Common side effects, such as dyspnea, cough and hoarseness, are dependent on the intensity of stimulation; they have been reported to diminish with time. To minimize patient discomfort, the stimulus intensity is typically slowly increased over 2 week intervals until a balance is found between the maximum stimulus intensity and the patients' willingness to accept any side effects. See M. S. George, and G. Aston-Jones, “Noninvasive techniques for probing neurocircuitry and treating illness: Vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct cunent stimulation (tDCS),” Neuropsychopharmacology REVIEWS, vol. 35, pp. 301-316, 2010. The current method of parameter optimization can be complex and time consuming for the patient and physician. Table 1 summarizes a protocol for stimulus parameter adjustments after implantation. Table 2 summarizes available device settings and common variations used in treating depression and epilepsy. See D. M. Labiner, and G. L. Ahern, “Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings,” Acta Psychiatrica Scandinavica, vol. 115, pp. 23-33, 2007.
TABLE 1Suggested stimulus parameter adjustment protocol(Labiner and Ahern, 2007)To increase efficacyTo manage side effects1. ≥2 weeks after implant, increase1. Reduce output current   output current by 0.25-0.5 mA at 2-week2. Reduce pulse width   intervals to maximum tolerated level,3. Reduce frequency   typically 1.0-2.0 mA.4. Reduce ON time2. If no response after 1-3 months at   maximum tolerated output current,   gradually increase duty cycle (increase   ON time, decrease OFF time)
TABLE 2Overview of available VNS stimulus parameter settings (Labiner and Ahern, 2007)StimulationProgrammableProgrammingRecommendedTypical targetparametersrangestepsinitial valuesvaluesOutput current0-35 mA0.25 mA0.25 mA1.0-2 mAFrequency1-30 Hz11, 2, 5, 10, 15, 20, 25, 30 Hz20 Hz220-30 Hz30 Hz3Pulse width130-1000 μs130, 250, 500, 750, 1000 μs250-500 μs250-500 μsDuty cycle10-100%4Function of signal ON, OFF times10%10%Signal ON time7-60 s7, 14, 21, 30, 60 s30 s30 sSignal OFF time0.2-180 min55-60 min, 5-min steps5 min5 min50-180 min, 30-min steps1Values below 5 Hz should be avoided.2In depression.3In epilepsy.4Duty cycles greater than 50% have resulted in nerve damage in laboratory animals [26].5Setting OFF time to 0.0 min turns off time pulse generator.
Many of the VNS studies published to date conclude that VNS imparts its antiepileptic and antidepressive effects through activation of vagal afferent fibers. This is a logical conclusion, because: 1) the device is intended to treat neuronal network-level disorders in the CNS, 2) vagal afferent fibers primarily project to the NTS and onward to the LC, where a chemical lesion was shown to significantly attenuate VNS-mediated anticonvulsive activity, and 3) evoked potentials from VNS have been repeatedly observed in neural recording/imaging studies. See S. E. Krahl, K. B. Clark, D. C. Smith et al., “Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation,” Epilepsia, vol. 39, no. 7, pp. 709-714, 1998. However, the conclusion that VNS works by activating unmyelinated C fibers of the vagus nerve is debated, because 1) destruction of C fibers does not destroy the antiepileptic effect of VNS and 2) stimuli found to be effective in epilepsy are of insufficient strength to activate the unmyelinated, afferent C fibers. See M. S. George, Z. Nahas, D. E. Bohning et al., “Vagus nerve stimulation therapy: A research update,” Neurology, vol. 59, no. Suppl. 4, pp. S56-S61, 2002; D. M. Woodbury, and J. W. Woodbury, “Effects of vagal stimulation on experimentally induced seizures in rats,” Epilepsia, vol. 31, no. Suppl. 2, pp. S7-S19, 1990; and M. S. Evans, S. Verma-Ahuja, D. K. Naritoku et al., “Intraoperative human vagus nerve compound action potentials,” Acta Psychiatrica Scandinavica, vol. 110, pp. 232-238, 2004.
Research on communication pathways between the immune, endocrine and central nervous systems in the past several decades suggests alternative, under-recognized pathways through which VNS may impart an antidepressive effect. A series of discoveries by Dr. Kevin J. Tracey and colleagues in the last decade led his startup company, SetPoint Medical, to begin clinical trials of VNS for the treatment of inflammation associated with autoimmune disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (MD). See E. Singer, “Technology Review: Neural Stimulation for Autoimmune Diseases,” A startup is developing an implanted stimulator to treat such illnesses as arthritis and inflammatory bowel disease, 2010]. The work that led to the discovery of VNS' potential in treating inflammatory disorders was a demonstration that VNS prevents sepsis by inhibiting macrophage activation and reducing proinflammatory cytokine (PIC) production. See L. V. Borovikova, S. Ivanova, M. Zhang et al., “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin,” Letters to Nature, vol. 405, pp. 458-462, 2000. It was found that VNS modulated a previously unrecognized communication pathway between the immune system and CNS, named the cholinergic anti-inflammatory reflex. See K. J. Tracey, “The inflammatory reflex,” NATURE, vol. 420, pp. 853-859, 2002; K. J. Tracey, “Physiology and immunology of the cholinergic anti-inflammatory pathway,” The Journal of Clinical Investigation, vol. 117, no. 2, pp. 289-296, 2007; and K. J. Tracey, “Reflex control of immunity,” Nature Review Immunology, vol. 9, pp. 418-428, 2009. The afferent arm of the reflex senses PICs and/or pathogenic antigens at the site of injury or infection and relays the information to the NTS. Although the precise relationship is still unknown, the NTS signals the DMN of the vagus in proportion to the level of sensory input into the NTS. The DMN then reflexively increases efferent output to vagal nerve innervated structures, where ACh is released. See Id. Mainly through vagal projections to the spleen, ACh imparts a graded anti-inflammatory effect by binding to the a7 nicotinic acetylcholine receptors (a7nAChR) on PIC-producing immune cells (e.g., macrophages). When ACh binds to the a7nAChR, PIC production and release is suppressed. Therefore, VNS-mediated modulation of the cholinergic anti-inflammatory reflex effectively suppresses the over-active immune system in patients with autoimmune inflammatory disorders. The cholinergic anti-inflammatory reflex is a significant discovery, because it imparts tonic, rapid and direct neural control over immune system activity. See E. Singer, “Technology Review: Neural Stimulation for Autoimmune Diseases,” A startup is developing an implanted stimulator to treat such illnesses as arthritis and inflammatory bowel disease, 2010; L. V. Borovikova, S. Ivanova, M. Zhang et al., “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin,” Letters to Nature, vol. 405, pp. 458-462, 2000; and K. J. Tracey, “Reflex control of immunity,” Nature Review Immunology, vol. 9, pp. 418-428, 2009. Due to its accessibility in the vagus nerve, any abnormality in its function can theoretically be treated with VNS. However, as with VNS for TLE and MDD, the interplay between the applied stimulus parameters and associated effects must be better understood for VNS to realize its full therapeutic potential.
Rheumatoid arthritis and MD (e.g., Crohn's disease and ulcerative colitis) are associated with high rates of comorbid depression. See E. Fuller-Thomson, and J. Sulman, “Depression and inflammatory bowel disease: Findings from two nationally representative Canadian surveys,” Inflamm Bowel Dis, vol. 12, pp. 697-707, 2006; and L. M. Kurina, M. J. Goldacre, D. Yeates et al., “Depression and anxiety in people with inflammatory bowel disease,” J Epidemiol Community Health, vol. 55, pp. 716-720, 2001. It is not known whether depression precedes the disorders or results from the effects of the disorders, but depressed patients with MD typically experience a depressive episode within a year of their MD diagnosis. See Id. Table 3 provides an overview of other chronic medical conditions associated with high rates of comorbid depression. See D. L. Evans, D. S. Chamey, L. Lewis et al., “Mood disorders in the medically ill: Scientific review and recommendations,” Biol Psychiatry, vol. 58, pp. 175-189, 2005. A key factor common to many, if not all of the conditions, is inflammation. It is proposed that an excessive or prolonged inflammatory response, due to an autoimmune disease, persistent/recurrent infection, or injury, can lead to a misdiagnosis of refractory MDD. These individuals may not respond well to conventional antidepressant therapy, because the drugs are not targeting the source of the symptoms: Cytokine-induced depression (i.e., “sickness behavior”). See C. L. Raison, and A. H. Miller, “Depression in cancer: New developments regarding diagnosis and treatment,” Biol Psychiatry, vol. 54, pp. 283-294, 2003. The depressive symptoms may be alleviated in these individuals by reducing circulating levels of PICs, which are ultimately responsible for many of the depressive symptoms due to their effects on key regions of the brain that control emotion, mood and motivation. See G. Cizza, A. H. Marques, F. Eskandan et al., “Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: The POWER study,” Biol Psychiatry, vol. 64, pp. 907-911, 2008; and Y. Dowlati, N. Hermann, W. Swardfager et al., “A meta-analysis of cytokines in major depression,” Biol Psychiatry, vol. 67, pp. 446-457, 2010. Others have worked out many of the neural-immune communication pathways and their relationship to depression. Tracey and colleagues are exploring VNS for autoimmune inflammatory disorders. Since VNS reduces inflammation in inflammatory disorders associated with high rates of comorbid depression (e.g., RA and MD), VNS-mediated modulation of the cholinergic anti-inflammatory reflex may be an important component of the therapeutic mechanisms of VNS in refractory MDD patients. A review of the literature identified one other individual who has considered the link between modulation of the cholinergic anti-inflammatory reflex, inflammation and depression: Undurti N. Das, a specialist in metabolic syndrome pathophysiology. See U. N. Das, “Vagus nerve stimulation, depression, and inflammation,” Neuropsychopharmacology, vol. 32, pp. 2053-2054, 2007. However, he has not fully developed the hypothesis or attempted to test it.
TABLE 3Comorbid depression in chronic illness (Adapted from Evans et al.)DepressionPrevalenceChronic IllnessRate (%)ReferenceGeneral Population (no10.3Kessler et al., 1994known illness)Parkinson's Disease 4-75McDonald et al., 2003Epilepsy20-55Kanner, 2003(Recurrent/Refractory)Pain30-54Campbell et al., 2003Rheumatoid Arthritis42  Bruce, 2008Alzheimer's Disease30-50Lee and Lyketsos, 2003Obesity20-30Stunkard et al., 2003Cancer22-29Raison and Miller, 2003Cardiac Disease17-27Rudisch and Nemeroff, 2003See R. C. Kessler, K. A. McGonagle, S. Zhao et al., “Lifetime and 12-month prevalence of DSM-Ill-R psychiatric disorders in the United States,” Arch Gen Psychiatry, vol. 51, pp. 8-19, 1994; W. M. McDonald, I. H. Richard, and M. R. DeLong, “The prevalence, etiology and treatment of depression in Parkinson's disease,” Biol Psychiatry, vol. 54, pp. 363-375, 2003; A. M. Kanner, “Depression in epilepsy: Prevalence, clinical semiology, pathogenic mechanisms, and treatment,” Biol Psychiatry, vol. 54, pp. 388-398, 2003; L. C. Campbell, D. J. Clauw, and F. J. Keefe, “Persistent pain and depression: A biopsychosocial perspective,” Biol Psychiatry, vol. 54, pp. 399-409, 2003; T. 0. Bruce, “Comorbid depression in rheumatoid arthritis: Pathophysiology and clinical implications,” Curr Psychiatry Rep., vol. 10, no. 3, pp. 258-264, 2008; H. B. Lee, and C. G. Lyketsos, “Depression in Alzheimer's disease: Heterogeneity and related issues,” Biol Psychiatry, vol. 54, pp. 353-362, 2003; A. J. Stunkard, M. S. Faith, and K. C. Allison, “Depression and obesity,” Biol Psychiatry, vol. 54, pp. 330-337, 2003; and B. Rudisch, and C. B. Nemeroff, “Epidemiology of comorbid coronary artery disease and depression,” Biol Psychiatry, vol. 54, pp. 227, 2003.
In addition, depression is among the top predictors of mortality and substandard daily functioning in North America, second only to cardiovascular disorders. See K. B. Wells, A. Stewart, R. D. Hays et al., “The functioning and well-being of depressed patients: Results from the medical outcomes study,” JAMA, vol. 262, pp. 914-919, 1989. Due to conventional symptom-based classification schemes and an incomplete understanding of the disorder, the term “depression” is used to describe a broad set of disparate pathologies sharing a common set of symptoms—pathologies that manifest as abnormal control and expression of mood and emotion. See R. J. Davidson, D. Pizzagalli, J. B. Nitschke et al., “Depression: Perspectives from affective neuroscience,” Annu. Rev. Psychol., vol. 53, pp. 545-574, 2002. Depressed individuals may experience a dispirited mood, a lowered sense of enthusiasm or enjoyment with routine tasks (i.e., anhedonia), a disrupted sleep schedule, altered behavior, appetite, or weight, a change in the speed of muscle movements, a decreased energy level, an inability to focus, thoughts of worthlessness or guilt, and thoughts of death or suicide over an extended period of time. See “American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision,” Fourth ed., Washington, D.C.: R. R. Donnelly & Sons Company, 2000; and K. Kroenke, R. L. Spitzer, and J. B. W. Williams, “The PHQ-9: Validity of a brief depression severity measure,” J Gen Intern Med, vol. 16, pp. 606-613, 2001. Current treatment measures do not effectively control symptoms in most depressed patients, especially the estimated 4 million Americans with the severe treatment-resistant subtype known as refractory major depressive disorder. See Cyberonics, “About treatment resistant depression,” VNS Therapy, Cyberonics, ed., 2007; and R. C. Kessler, P. Berglund, O. Demler et al., “Lifetime prevalance and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication,” Arch Gen Psychiatry, vol. 62, no. 6, pp. 593-602, 2005.
Refractory MDD is characterized by recurrent, long-lasting cycles of severe, often suicidal depressive episodes that do not remit using multiple types of antidepressant therapies. A depressive episode persists for up to a year, significantly impairing the health and daily activities of the afflicted. See L. L. Judd, H. S. Akiskal, J. D. Maser et al., “A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders,” Arch Gen Psychiatry, vol. 55, pp. 694-700, 1998; and H. K. Manji, W. C. Drevets, and D. S. Charney, “The cellular neurobiology of depression,” Nature Medicine, vol. 7, no. 5, pp. 541-547, 2001. In fact, the net loss of productivity stemming from the disorder costs the United States an estimated 83 billion dollars each year. See J. C. Coyne, S. Fechner-Bates, and T. L. Schwenk, “Prevalence, nature, and comorbidity of depressive disorders in primary care,” Gen Hosp Psychiatry, vol. 16, pp. 267, 1994. Even with the best FDA-approved antidepressant treatments, the majority of MDD patients will inevitably suffer from multiple depressive episodes during their lifetime. See R. C. Kessler, P. Berglund, O. Demler et al., “The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R),” JAMA, vol. 289, no. 23, pp. 3095-3105, 2003; and T. I. Mueller, A. C. Leon, M. B. Keller et al., “Recurrence after recovery from major depressive disorder during 15 years of observational follow-up,” Am J Psychiatry, vol. 156, no. 7, pp. 1000-1006, 1999. To make matters worse, each recurrent depressive episode puts the patient at a 16% increased risk for developing an additional depressive episode during their lifetime, often presenting with more severe symptoms than previous episodes. See D. A. Solomon, M. B. Keller, A. C. Leon et al., “Multiple Recurrences of Major Depressive Disorder,” Am J Psychiatry, vol. 157, no. 2, pp. 229-233, 2000.
Stimulation-based technologies, designed to electrically or chemically modulate abnormal neural activity, are emerging as potential therapeutic options for refractory MDD patients. However, the expected treatment efficacies of these technologies, as with all antidepressant treatments, are burdened by an incomplete understanding of the pathophysiology of depressive disorders and a lack of reproducible and quantifiable biological markers (i.e., biomarkers) of depressed states (Antidepressant treatment response is still subjectively evaluated using patient-reported symptom relief, effectively ignoring the prospect of using objectively quantified, depression-linked biomarker levels to quantify antidepressant responses and to optimize treatment). With modern research tools, additional structural, functional, and genetic abnormalities associated with depression are discovered each year. Concomitantly, several quantifiable genetic, biochemical, and bioelectric diagnostic markers of depression are emerging. Similar discoveries in the epilepsy research field sparked interest in closed-loop neuroprostheses, where biological indicators of an impending seizure are used to determine the time at which an electrical or chemical stimulus must be applied to stop a seizure. See D. Dumitriu, K. Collins, R. Alterman et al., “Neurostimulatory therapeutics in management of treatment-resistant depression with focus on deep brain stimulation,” Mount Sinai Journal of Medicine, vol. 75, pp. 263-275, 2008. This process, known as responsive neurostimulation, is unique to closed-loop devices. It is intended to replace continuous or periodic open-loop stimulation designs so that tailored therapy, based on quantifiable symptom-linked biomarker abnormalities, is provided in a dose dependent manner only when it is necessary. See W. K. Goodman, and T. R. Insel, “Deep brain stimulation in psychiatry: Concentrating on the road ahead,” Biol Psychiatry, vol. 65, pp. 263-266, 2009; and F. T. Sun, M. J. Morrell, and R. E. Wharen, “Responsive cortical stimulation for the treatment of epilepsy,” Neurotherapeutics, vol. 5, no. 1, pp. 68-74, 2008.
Therefore, there is a need for a system and method to improve the efficacy of existing VNS therapy in patients suffering from refractory MDD with additional benefits for patients with refractory TLE through a system implementing closed-loop stimulus parameter optimization algorithms